title: Effect of cell-penetrating peptides on the nasal absorption of insulin.
abstract: The goal of this study was to evaluate whether cell-penetrating peptides (CPPs) affect the nasal absorption of insulin. L- or D-forms of penetratin, or the L- or D-forms of octaarginine (L- or D-R8), was used as first time for nasal insulin delivery. Furthermore, the concentration of lactate dehydrogenase (LDH) in nasal lavage fluid was determined and a histopathological study of nasal respiratory epithelium was conducted. CPPs dramatically increased nasal insulin absorption, and it was more pronounced for L- and D-penetratin than L- or D-R8. L-penetratin was the most effective promoter of insulin absorption compared with others CPPs. A dose-dependent relationship of L-penetratin and insulin bioavailability was statically significant. The pharmacological availability and bioavailability of nasally administered insulin was up to 76.7% and 50.7% relative to the subcutaneous route, respectively. In contrast, increasing the D-penetratin concentration decreased the efficiency of nasal insulin absorption. There was no significant difference in the release of LDH in nasal lavage fluid and the integrity of nasal respiratory epithelium when L-penetratin was present. In conclusion, these data demonstrate that L-penetratin markedly increased the permeability of insulin across the nasal membrane without causing detectable damage to the integrity of cells in the nasal respiratory mucosa.
authors.affiliation: Department of Pharmaceutics, Hoshi University, Shinagawa, Tokyo, Japan.
authors.forename: El-Sayed
authors.initials: el-S
authors.lastname: Khafagy
authors.forename: Mariko
authors.initials: M
authors.lastname: Morishita
authors.forename: Koichi
authors.initials: K
authors.lastname: Isowa
authors.forename: Jun
authors.initials: J
authors.lastname: Imai
authors.forename: Kozo
authors.initials: K
authors.lastname: Takayama
mesh_terms: D000042:Absorption / Q000187:drug effects; D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D057846:Cell-Penetrating Peptides; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism*; D009666:Nose / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013657:Taurodeoxycholic Acid / Q000494:pharmacology
chemical_list: D000277:Adjuvants, Pharmaceutic; D001786:Blood Glucose; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D007004:Hypoglycemic Agents; D007328:Insulin; D009842:Oligopeptides; D010455:Peptides; C500307:octa-arginine peptide; D013657:Taurodeoxycholic Acid; C414409:penetratin; D007770:L-Lactate Dehydrogenase